Familial hypercholesterolemia (FH) is one of the commonest simply inherited disorders of man, yet is seldom effectively treated. Standard diet or drug therapy usually produce minimal to moderate reductions in serum cholesterol, while plasmapheresis and surgical intervention often fair little better. Although conventional diets have achieved little success in the treatment of FH, it is well known that dietary factors may influence endogenous lipoprotein metabolism. Of particular interest are the effects of glucose-rich diets or blood lipids and lipid synthesis. Animal studies have shown that glucose-supplemented diets lower circulating levels of cholesterol and inhibit cholesterol synthesis. Studies in normocholesterolemic man also indicate that oral or parenteral glucose administration significantly reduce blood cholesterol. In patients with homozygous FH, parenteral alimentation with glucose-supplemented diets also reduce plasma cholesterol. We recently found that oral administration of a glucose-rich diet (VivonexR) markedly decreased plasma total and low density lipoprotein cholesterol in a young homozygous FH patient. Plasma insulin levels rose substantially during treatment. In another honozygous patient, with elevated basal cholesterol and bile acid synthesis, Vivonex administration markedly decreased fecal steroid excretion, but produced minimal changes in plasma lipid and lipoprotein levels. In both patients, treatment was well tolerated and was associated with regression of xanthomata. The specific aims of this proposal are to evaluate further the effectiveness, safety and mechanism of the cholesterol-lowering effect of high glucose diets in normal subjects and patients with FH. In addition, by these means we will test an innovative dietary approach to the treatment of FH.